Synthesis of Bile Acid Dimers Linked with 1,2,3-Triazole Ring at C-3, C-11, and C-24 Positions

Abstract

1,3-Dipolar cycloaddition of propargyl ester of a bile acid to an azide group attached at different positions of another bile acid gave three new 1,2,3-triazole-containing dimeric analogues in excellent yields.

bile acids - steroidal dimers - click chemistry - 1,3-dipolar cycloaddition - 1,2,3-triazole

References

1a Davis AP. Chem. Soc. Rev.  1993,  243 

1b Li Y. Dias JR. Chem. Rev.  1997,  97:  283 

1c Wallimann P. Marti T. Fürer A. Diederich F. Chem. Rev.  1997,  97:  1567 

1d Kolehmainen E. Tamminen J. Molecules  2001,  6:  21 

1e Virtanen E. Kolehmainen E. Eur. J. Org. Chem.  2004,  3385 

2 Bortolini O. Cora V. Fantin G. Medici A. Chem. Lett.  1996,  335 

3 Burrows CJ. Sauter RA. J. Inclusion Phenom.  1987,  5:  117 

4 Kinneary JF. Roy TM. Albert JS. Yoon H. Wagler TR. Shen L. Burrows CJ. J. Inclusion Phenom.  1989,  7:  155 

5 McKenna J. McKenna JM. Thornthwaite DW. J. Chem. Soc., Chem. Commun.  1977,  809 

6a Tamminen J. Kolehmainen E. Haapala M. Linnanto J. Synthesis  2000,  1464 ; and references cited therein

6b Pandey PS. Rai R. Singh RB. J. Chem. Soc., Perkin Trans. 1  2002,  918 ; and references cited therein

6c Pandey PS. Singh RB. Tetrahedron  2002,  58:  355 

7 Davis AP. Wareham RS. Angew. Chem. Int. Ed.  1999,  38:  2978 ; and references cited therein

8a Kohmoto S. Sakayori K. Kishikawa K. Yamamoto M. J. Chem. Soc., Perkin Trans. 2  1999,  833 

8b Potluri VK. Maitra U. J. Org. Chem.  2000,  65:  7764 ; and references cited therein

9 Salunke DB. Hazra BG. Pore VS. Bhat MK. Nahar PB. Deshpande MV. J. Med. Chem.  2004,  47:  1591 

10a Lakhvich FA. Lis LG. Akhrem AA. Russ. Chem. Rev.  1984,  53:  582 

10b Burbiel J. Bracher F. Steroids  2003,  68:  287 

10c Fouace S. El kihel L. Dherbomez M. Letourneux Y. Bioorg. Med. Chem. Lett.  2001,  11:  3011 

11a Odds FC. Brown AJP. Gow NAR. Trends Microbiol.  2003,  11:  272 ; and references cited therein

11b Cooper AB. Wright JJ. Ganguly AK. Desai J. Loebenberg D. Parmeqiani R. Feingold DS. Sud IJ. J. Chem. Soc., Chem. Commun.  1989,  898 

12a Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 

12b Tornoe CW. Christensen C. Meldal M. J. Org. Chem.  2002,  67:  3057 

13 Suarez PL. Gandara Z. Gomez G. Fall Y. Tetrahedron Lett.  2004,  45:  4619 

14 Suh BC. Jeon HB. Posner GH. Silverman SM. Tetrahedron Lett.  2004,  45:  4623 

15 Chittaboina S. Xie F. Wang Q. Tetrahedron Lett.  2005,  46:  2331 

16 Davis AP. Perez-Payan MN. Synlett  1999,  991 

17

Typical Experimental Procedure. A solution of azide (1 mmol) and propargyl ester of bile acid (0.95 mmol) in t-BuOH (10 mL) was stirred at 60 °C for 15 min. Then, CuSO₄·5H₂O (5 mol% in 0.5 mL of H₂O) and sodium ascorbate (20 mol% in 0.5 mL of H₂O) were added to the reaction mixture and it was stirred at 60-65 °C for 3-12 h. The solvent was evaporated under reduced pressure to afford a crude product, which on purification by column chromatography on silica gel gave pure dimeric compounds containing 1,2,3-triazole moiety in 92-96% yield.
Spectral Data of Compound 8.
Yield 92%; mp 100-102 °C (EtOAc-hexane); [α]_D ³¹ = +11.0 (c 0.6, CHCl₃); TLC: R _f = 0.56 (MeOH-CH₂Cl₂, 1:9). IR (CHCl₃): 3431, 1728 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.66 (s, 3 H), 0.70 (s, 3 H), 0.91-1.00 (12 H), 3.61 (m, 1 H), 3.66 (s, 3 H, OCH₃), 3.96 (br s, 1 H), 4.02 (br s, 1 H), 4.47 (m, 1 H), 5.20 (s, 2 H), 7.68 (s, 1 H, triazole H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 12.6, 17.2, 23.0, 23.1, 23.6, 25.9, 26.1, 26.8, 27.0, 27.4, 27.9, 28.6, 30.3, 30.6, 30.8, 31.1, 33.5, 33.6, 33.8, 34.0, 34.2, 35.1, 35.6, 35.9, 36.3, 42.0, 42.6, 46.4, 46.5, 47.0, 47.2, 47.9, 48.2, 51.4, 57.5, 61.0, 71.6, 72.9, 122.1, 142.2, 174.1, 174.6 ppm. MS (LC-MS): m/z calcd: 862.62 [M⁺ + 1]; found: 862.8 [M⁺ + 1], 884.8 [M⁺ + Na]. Anal. Calcd for C₅₂H₈₃N₃O₇: C, 72.44; H, 9.70; N, 4.87. Found: C, 72.17; H, 10.02; N, 4.60.

18 Li C. Peters AS. Meredith EL. Allman GW. Savage PB. J. Am. Chem. Soc.  1998,  120:  2961 

19

Spectral Data of Compound 13.
Yield 96%; mp 136-138 °C (EtOAc-hexane); [α]_D ³¹ = +9.84 (c 0.61, CHCl₃); TLC: R _f = 0.52 (MeOH-CH₂Cl₂, 0.5:9). IR (CHCl₃): 3419, 1728 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.65 (s, 3 H), 0.66 (s, 3 H), 0.90-0.98 (12 H), 3.59 (m, 2 H), 3.96 (br s, 2 H), 4.31 (t, J = 7.07 Hz, 2 H, OCH₂), 5.21 (s, 2 H), 7.60 (s, 1 H, triazole H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 12.3, 17.1, 17.4, 23.0, 23.6, 26.0, 26.9, 27.1, 27.5, 28.4, 30.2, 30.6, 31.0, 32.4, 33.3, 33.9, 35.1, 35.8, 36.1, 42.0, 46.3, 46.8, 47.9, 50.7, 57.3, 60.3, 63.5, 71.4, 72.9, 123.6, 142.7, 174.1 ppm. MS (LC-MS): m/z calcd: 834.63 [M⁺ + 1]; found: 834.7 [M⁺ + 1], 856.7 [M⁺ + Na]. Anal. Calcd for C₅₁H₈₃N₃O₆: C, 73.43; H, 10.03; N, 5.04. Found: C, 73.11; H, 9.82; N, 4.82.

20 Salunke DB. Hazra BG. Gonnade RG. Bhadbhade MM. Pore VS. Tetrahedron  2005,  61:  3605 

21

Spectral Data of Compound 16.
Yield 92%; mp 156-157 °C (EtOAc-hexane); [α]_D ³¹ = +20.0 (c 0.61, CHCl₃); TLC: R _f = 0.4 (MeOH-CH₂Cl₂, 0.5:9). IR (CHCl₃): 3411, 1728, 1674 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.67 (s, 3 H), 0.73 (d, J = 5.93 Hz, 3 H), 0.89 (s, 3 H), 0.96 (d, J = 5.69 Hz, 3 H), 1.18 (s, 3 H), 1.27 (s, 3 H), 2.00 (s, 3 H), 2.10 (s, 3 H), 3.45 (m, 1 H), 3.66 (s, 3 H, OCH₃), 3.84 (br s, 1 H), 3.96 (br s, 1 H), 3.40 (m, 1 H), 5.02 (br s, 1 H) 5.24 (d, J = 2.02 Hz, 2 H, OCH₂), 5.91 (d, J = 9.98 Hz, C-11 H attached to triazole), 7.83 (s, 1 H, triazole H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 11.2, 12.4, 17.2, 18.4, 21.2, 21.3, 22.5, 23.2, 24.0, 26.5, 27.1, 27.4, 28.2, 29.5, 30.1, 30.3, 30.8, 30.9, 31.0, 31.2, 34.6, 34.7, 35.1, 35.2, 35.4, 37.4, 38.1, 39.6, 41.5, 41.7, 42.2, 44.2, 46.5, 46.8, 47.4, 51.4, 52.4, 56.5, 57.4, 65.7, 68.3, 70.4, 71.9, 72.9, 73.2, 126.0, 142.7, 169.8, 170.5, 174.0, 174.3, 204.1 ppm. MS (LC-MS): m/z calcd: 992.61 [M⁺ + 1]; found: 992.7 [M⁺ + 1], 1014.7 [M⁺ + Na]. Anal. Calcd for C₅₆H₈₅N₃O₁₂: C, 67.78; H, 8.63; N, 4.23. Found: C, 67.43; H, 8.71; N, 3.97.